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Entry Inhibitors

July 2004

Entry inhibitors are a new class of anti-HIV drugs that work by blocking the virus' ability to infect a cell. There are two general types of entry inhibitors: fusion inhibitors and attachment inhibitors. They may be joined by a third type in future years.

Enfuvirtide (T-20, Fuzeon), a fusion inhibitor approved by the Food and Drug Administration in 2003, is the first of this new class available for wide scale use. While enfuvirtide has proven to be potent, its side effects, mostly associated with the fact that it has to be injected with a syringe, have discouraged many people from using it. Still, others have been denied access because of the extremely high cost of the drug, which prevents many states from including it in their AIDS Drug Assistance Programs (ADAP). For more information on enfuvirtide, call Project Inform's toll-free hotline at 1-800-822-7422.

Many believe the greater promise for entry inhibitors will be realized with small molecule drugs. When large molecule drugs, like enfuvirtide, are taken orally, the digestive process breaks them into smaller pieces, thus rendering them ineffective. Therefore, they must be taken by injection. Small molecules drugs, however, are unaltered by the digestive system and can be taken by mouth, avoiding the problems associated with injections. Several are in development, including six that are in human studies, which we report on here.

HIV viral entry involves four steps. First, the virus attaches to the CD4+ protein, a receptor that appears on certain cells of the immune system. Then, it binds to a second surface protein on these cells, called a co-receptor. The most common co-receptors for HIV are CCR5 and CXCR4. Once it's anchored to the two receptors, the virus fuses its outer coat to the coat of the cell. Lastly, HIV sheds its own coat and injects its genetic material from its core into the cell.

There are compounds in development that target each of these entry steps. Most are still in test tube studies. The six entry inhibitors currently in human studies can be divided into two categories -- those that block the first step (virus attachment to the CD4+ protein) and those that block the second step (binding to a co-receptor).


The promise of entry inhibitors, especially small molecules, has many companies working on their own novel drugs. Many are still in pre-clinical development, and are years away from being available. However there are a number of promising candidates already in human studies. If these continue to show promise, some might reach wider human use within two or two and a half years.

People living with HIV need drugs that address new targets, which are easier to take and have fewer side effects. Entry inhibitors hold promise in these ways, but as always, the proof will come from clinical studies.

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